1. Field of the Invention
This invention relates to 1-azatricyclic-4-benzylpiperazines, and to compounds that bind to dopamine receptors. This invention also relates to pharmaceutical compositions comprising such compounds and also to the treatment of central nervous system (CNS) diseases, particularly the treatment or prevention of psychotic disorders such as to schizophrenia. Additionally this invention relates to the use of compounds as probes for the localization of dopamine receptors in tissue sections.
2. Description of the Related Art
The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to blockade of D2 receptors in the striatal region of the brain. The dopamine D4 receptor subtype has been identified and cloned. Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D4 receptor may play a major role in the etiology of schizophrenia. The dopamine D4 receptor shares sequence homology with dopamine D2 and D3 receptors, however the D4 receptor possesses a unique pharmacological profile. Selective D4 antagonists, including the marketed antipsychotic chlozapine, are considered effective antipsychotics free from the neurological side effects displayed by conventional neuroleptics. Compounds that possess a 10-fold or more higher affinity for dopamine D4 receptors than D2 receptors are considered particularly desirable as antipsychotics.
Since dopamine D4 receptors are concentrated in the limbic system which controls cognition and emotion, compounds which interact with these receptors have utility in the treatment of cognitive disorders. Such disorders include the cognitive deficits which are a significant component of the negative symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders involving memory impairment or attention deficit disorder can also be treated with compound that interact specifically with the dopamine D4 receptor subtype.
This invention provides 1-azatricyclic-4-benzylpiperazine compounds that bind, preferably with high affinity and selectivity, to the D4 receptor subtype, including human D4 receptors. These compounds are therefore useful in treatment of a variety of neuropsychological disorders, such as, for example, schizophrenia, psychotic depression and mania. Other dopamine-mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D4 receptors.
Thus, the invention provides compounds of Formula I (shown below), and pharmaceutical compositions comprising compounds of Formula I.
The invention further comprises methods of treating patients suffering from CNS disorder with a therapeutically effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from CNS disorder with a therapeutically effective amount of a compound of the invention is encompassed by the invention. Particularly methods for the treatment and/or prevention of neuropsychological or affective disorders, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents are included. In addition, the compounds of the invention are useful in treatment of depression, memory-impairment or Alzheimer""s disease by modulation of D4 receptors which selectively exist in limbic areas known to control emotion and cognitive functions. Further, the compounds of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., substance abuse and obsessive compulsive disorder. These compounds are also useful in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents.
Accordingly, a broad aspect of the invention is directed to compounds of Formula I: 
or a pharmaceutically acceptable salt thereof, wherein
A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C1-C6)hydrocarbylamino, aminosulfonyl, C1-C6 hydrocarbylaminosulfonyl, di(C1-C6)hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C1-C6 hydrocarbyl, trifluoromethoxy, C3-C6 cyclohydrocarbyl, and C1-C6 alkoxy;
R5 and R6 are the same or different and represent hydrogen or C1-C6 hydrocarbyl; and
R2 represents hydrogen, halogen, hydroxy, amino, mono- or di(C1-C6)hydrocarbylamino, aminosulfonyl, C1-C6 hydrocarbylaminosulfonyl, di(C1-C6)hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, C1-C6 hydrocarbyl, trifluoromethoxy, C3-C6 cyclohydrocarbyl, or C1-C6 alkoxy; and
n is 0, 1, or 2.
The invention encompasses the compounds of Formula I described above.
In preferred compounds of formula I,
A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C1-C6)alkylamino, aminosulfonyl C1-C6 alkylaminosulfonyl, di (C1-C6) alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C1-C6) alkyl, trifluoromethoxy, C3-C6 cycloalkyl, and C1-C6 alkoxy;
R5 and R6 are the same or different and represent hydrogen or C1-C6 alkyl; and
R2 represents hydrogen, halogen, hydroxy, amino, mono- or di(C1-C6)alkylamino, aminosulfonyl, C1-C6 alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C1-C6)alkyl, trifluoromethoxy, C3-C6 cycloalkyl, or C1-C6 alkoxy; and n is 0, 1, or 2.
In other preferred compounds of Formula I, n is 2;
A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C1-C6) alkylamino, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C1-C6)alkyl, trifluoromethoxy, C3-C6 cycloalkyl, and C1-C6 alkoxy;
R5 and R6 are the same or different and represent hydrogen or C1-C6 alkyl; and
R2 represents hydrogen, halogen, hydroxy, amino, mono- or di (C1-C6) alkylamino, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C1-C6)alkyl, trifluoromethoxy, C3-C6 cycloalkyl, or C1-C6 alkoxy.
More preferred compounds of Formula I are those where A is a group of the formula: 
where R3 and R4 independently represent hydrogen, halogen, hydroxy, amino, aminosulfonyl, C1-C6 alkylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, cyano, nitro, trifluoromethoxy, C1-C6 alkyl, or C1-C6 alkoxy.
These more preferred compounds are represented by Formula II herein. 
In preferred compounds of Formula II, R3 and R4 are the same or different and are C1-C3 alkyl, chloro, fluoro, bromo, or C1-C3 alkoxy. More preferably, in compounds of Formula II at least one of R3 and R4 is attached at the ortho or para position of the phenyl ring. Still more preferably, R2 in Formula II is hydrogen, fluoro, chloro, or C1-C2 alkyl.
In other preferred compounds of II, R2 is hydrogen. Such compounds are designated as compounds of Formula II-A hereinafter. In these compounds, R3 and R4 are the same or different and are C1-C3 alkyl, chloro, fluoro, bromo, or C1-C3 alkoxy. Preferably compounds of Formula II-A are those where at least one of R3 and R4 is in the ortho or para position of the phenyl ring. More preferred compounds of II-A are those wherein R5 and R6 independently represent hydrogen or C1-C2 alkyl. Still other more preferred compounds of II-A are those wherein at least one of R5 and R6 is methyl. Particularly preferred compounds of II-A are those where both R5 and R6 are methyl. Other particularly preferred compounds of Formula II-A are those where R5 is methyl and R6 is hydrogen.
The compounds of this invention may contain one or more asymmetric centers, e.g., carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, mixtures of diastereomers, or racemates or resolved enantiomers. Single enantiomers can be obtained as pure compounds or in enantiomeric excess by asymmetric synthesis or by resolution of the racemate. Resolution of the racemate can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formaic, citric, malic, maleic, fumaric, tartanic, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses prodrugs of the compounds of Formula I, e.g., acylated compounds and esters of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and prodrugs of the compounds encompassed by Formula I.
Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers. The invention includes all tautomeric forms of a compound.
Representative compounds of the invention are shown below in Table 1.
This invention provides 1-azatricyclic-4-benzylpiperazine compounds that bind with high affinity to dopamine receptors, particularly dopamine D4 receptors, including human dopamine D4 receptors. This invention also includes compounds that bind with high selectivity to dopamine receptors, particularly dopamine D4 receptors, including human dopamine D4 receptors. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of the invention with the dopamine D4 receptor results in the pharmaceutical utility of these compounds.
The invention further comprises methods of treating patients suffering from a CNS disorder with an amount of a compound of the invention sufficient to alter the symptoms of the disorder.
The diseases, conditions and disorders that can be treated using compounds and compositions according to the invention include, but are not limited to, schizophrenia, psychotic depression, mania, and the extrapyramidyl side effects associated with the use of a neuroleptic agent. Other dopamine-mediated disease such as Parkinsonism and tardive dyskinesias can also be treat directly or indirectly by modulation of dopamine receptors. Compounds of the invention are also useful in the treatment of depression, memory-impairment or Alzheimer""s disease by modulation of D4 receptors since these receptors are localized in areas known to control emotion and cognitive functions.
The invention also provides pharmaceutical compositions comprising compounds of the invention, including packaged pharmaceutical compositions, for treating disorders responsive to dopamine receptor modulation, especially dopamine D4 receptor modulation, e.g., treatment of schizophrenia, depression, tardive diskinesia or cognitive impairment by dopamine D4 receptor modulation. The packaged pharmaceutical compositions include a container holding a define quantity or unit dose, e.g., a therapeutically effective amount, of at least one compound of the invention and instructions (e.g., labeling) indicating how the contained compound is to be used in the patient, e.g., for treating a disorder responsive to dopamine receptor modulation.
The present invention also pertains to methods of inhibiting the binding of dopamine to dopamine D4 receptors which methods involve contacting a compound of the invention with cells expressing dopamine D4 receptors, wherein the compound is present at a concentration sufficient to inhibit dopamine binding to dopamine D4 receptors in vitro. This method includes inhibiting the binding of dopamine to dopamine D4 receptors in vivo, e.g., in a patient given an amount of a compound of Formula I that would be sufficient to inhibit the binding of dopamine to dopamine D4 receptors in vitro. The amount of a compound that would be sufficient to inhibit the binding of dopamine to the dopamine D4 receptor may be readily determined via a dopamine receptor binding assay, such as the assay described in Example 3. The dopamine receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat striatal homogenates or from cells expressing cloned human or monkey dopamine D4 receptors.
The compounds of this invention and labeled derivatives thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical agent to bind to the dopamine D4 receptor.
Radiolabeled derivatives of the compounds of this invention are also useful as radiotracers for positron emission tomography (PET) imaging or for single photon emission computerized tomography (SPECT).
Where the compounds of the present invention have asymmetric centers, the invention includes all of the optical isomers and mixtures thereof.
Compounds with carbon-carbon double bonds may occur in Z- and E-forms, and all the isomers of such compounds are included in the invention.
When any variable (e.g. C1-6 alkyl, C1-8 alkyl, A, R2, R5, or R6) occurs more than one time in any formula herein, its definition at each occurrence is independent of its definition at every other occurrence.
By xe2x80x9cC1-C6 alkylnxe2x80x9d in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms. Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
By xe2x80x9cC1-C6 hydrocarbylxe2x80x9d in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, optionally containing one or more carbon-carbon double or triple bonds. Examples of hydrocarbyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, vinyl, 2-pentene, and propargyl. When reference is made herein to C1-C6 hydrocarbyl containing one or two double or triple bonds it is understood that at least two carbons are present in the alkyl for one double or triple bond, and at least four carbons for two double or triple bonds.
By xe2x80x9cC1-C6 alkoxyxe2x80x9d or xe2x80x9clower alkoxyxe2x80x9d in the present invention is meant an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Preferred alkoxy groups herein are C1-C4 alkoxy groups.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to a C3-C7 cycloalkyl group attached to the parent molecular moiety through an alkyl group, as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl.
The term xe2x80x9chalogenxe2x80x9d indicates fluorine, chlorine, bromine, or iodine.
Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide.
The compounds of general Formula I may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
For administration to non-human animals, the compounds of Formula I may be added to the animals feed or drinking water. It will be convenient to formulate these animal feed and a drinking water compositions so that the animal consumes an appropriate quantity, e.g., a therapeutically effective amount, of the compound in its diet. It will also be convenient to in present the compound in a composition as a premix for addition to the feed or drinking water.
Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to in about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of schizophrenia, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have desirable pharmacological properties that include, but are not limited to, oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocytes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcovxc3xa1, et al. (Journal of Chromatography B (1996) volume 677, pages 1-27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition, (1998) volume 26, pages 1120-1127).
A representative synthesis of the compounds of the invention is presented in Scheme I. Those having skill in the art will recognize that the starting materials and reaction conditions may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases, protection of reactive functionalities may be necessary to achieve some of the transformations. In general, the need for such protecting groups as well as the conditions necessary to attach and remove such groups will be apparent to those skilled in the art of organic synthesis. 
In Scheme I, R2, R3, R4, R5 and R6 are as defined for Formula I. W is appropriate leaving group such as, for example, halogen or a sulfonate ester.
The starting indolines (5) are either commercially available, known, or capable of being prepared by the methods known in the art. Thus, to prepare compounds where R5 and R6 are alkyl, starting indoline (5) may be prepared by the methods of Azadi-Ardakani (J. Chem. Soc. Perkin Trans I. 1986, 1107). Azatricyclics 6 and 7 may be prepared according to the methods of Bass et al (J. Agri. Food Chem. 1981, 29, 576) or DeLombaert (Bioorg. Med. Chem. Lett. 1994, 7513). Preparation of intermediates containing an iodo leaving group (i.e., 8, where W=iodine) may be carried out by the method of Fisher (PCT application WO 95/16692). Other compounds may be prepared by procedures analogous to those described in literature.
The disclosures in this application of all articles and references, including patents, are incorporated herein by reference in their entirety.